This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Patients with low-grade lymphomas and Chronic Lymphocytic Leukemia (B-CLL) can experience a good quality of life with minimal treatment for several years. However the disease invariably progresses to become resistant to conventional treatment. Alternative approaches are based on stem cell transplantation, since the incoming immunity of the donor can attack the tumor (Graft versus lymphoma). This effect is produced by cells called T-lymphocytes that are one of the cellular components of the graft. However, these cells can also attack the normal organs of the patient to produce graft versus host disease which can be fatal. Using gene transfer technology, it maybe possible to take advantage of the tumor killing ability of the T-lymphocytes, whilst avoiding their capacity to cause damage to normal tissue. We propose taking the patients own T cells and putting into them a gene for an artificial structure (receptor) that will direct the T-lymphocytes to the tumor and allow them to kill it. These so-called chimeric antigen receptors (CAR) can be further changed by adding a second component that helps to trigger the T-lymphocytes once it sees the cancer target. We now propose to insert the genes for this CAR into patients T cells using a modified virus (Moloney retroviral vector) and giving the cells back to the patients. We will compare the T cells with the CAR containing the extra second component (CD28) with cells given a CAR that lacks this extra piece. The genetically modified T-lymphocytes will be infused into patients through a central line or directly into a vein. Patients will be treated in the clinic and will be monitored closely for several hours after infusion. We will collect samples of blood from peripheral blood at regular intervals. We will look for the safety, the persistence and the function of the cells we put into the patients. Ultimately we hope to get evidence that these CAR-T cells are effective at fighting the cancer. G